HopPathwayinCardiacDevelopment

Homeodomain transcription factors comprise a large family of DNA binding factors that regulate transcription and development. Many homeodomain genes arranged in genomic clusters determine anterior-posterior patterning, while others determine the fate of cells in specific tissues. The proliferation of cardiac myocytes and their differentiation early in development are both dependent on the coordinate expression and action of serum response factor (SRF), GATA4 (see GATA pathway) and the homeodomain factor Nkx2-5. All three of these factors are expressed in developing cardiomyocytes and induce expression of cardiac genes. Disruption of the Nkx2-5 gene in mice leads to embryonic lethality and defective cardiac development. SRF also plays a duel role in cardiac development, influencing both cardiomyocyte proliferation and differentiation depending on the stage and other signals that are present.In addition, the Hop (Homeodomain Only Protein) gene encodes a factor expressed early in cardiac development that is involved in cardiac differentiation. Hop inactivation in vertebrates leads to severe defects in cardiac development, acting downstream of Nkx2-5. Cardiac cells from mice lacking the Hop gene fail to exit the cell cycle in the normal manner, continuing to proliferate past the normal developmental stage. Many of the genes disregulated in the absence of Hop are involved in the cell cycle and are also targets of SRF. Although Hop is a homeodomain protein, it lacks a DNA-binding domain indicating that it must not regulate gene expression directly. Hop appears to regulate the expression of cardiac genes by binding to SRF and blocking DNA binding of SRF. The sequestration of SRF by Hop blocks the activation of cardiac genes, preventing normal cardiac development. The influence of Hop on the opposing processes of cardiomyocyte differentation and proliferation reflect the interaction of Hop with SRF and the duel role SRF plays. In early cardiac development, Hop opposes differentiation induction by SRF, while at later stages Hop opposes the proliferation induced by SRF.

Contributor:

REFERENCES: Chen F, Kook H, Milewski R, Gitler AD, Lu MM, Li J, Nazarian R, Schnepp R, Jen K, Biben C, Runke G, Mackay JP, Novotny J, Schwartz RJ, Harvey RP, Mullins MC, Epstein JA. Hop is an unusual homeobox gene that modulates cardiac development. Cell. 2002 Sep 20;110(6):713-23. Chen F, Kook H, Milewski R, Gitler AD, Lu MM, Li J, Nazarian R, Schnepp R, Jen K, Biben C, Runke G, Mackay JP, Novotny J, Schwartz RJ, Harvey RP, Mullins MC, Epstein JA. Hop is an unusual homeobox gene that modulates cardiac development. Cell. 2002 Sep 20;110(6):713-23. Moore ML, Wang GL, Belaguli NS, Schwartz RJ, McMillin JB. GATA-4 and serum response factor regulate transcription of the muscle-specific carnitine palmitoyltransferase I beta in rat heart. J Biol Chem. 2001 Jan 12;276(2):1026-33. Sepulveda JL, Belaguli N, Nigam V, Chen CY, Nemer M, Schwartz RJ. GATA-4 and Nkx-2.5 coactivate Nkx-2 DNA binding targets: role for regulating early cardiac gene expression. Mol Cell Biol. 1998 Jun;18(6):3405-15. Sepulveda JL, Vlahopoulos S, Iyer D, Belaguli N, Schwartz RJ. Combinatorial expression of GATA4, Nkx2-5, and serum response factor directs early cardiac gene activity. J Biol Chem. 2002 Jul 12;277(28):25775-82. Shin CH, Liu ZP, Passier R, Zhang CL, Wang DZ, Harris TM, Yamagishi H, Richardson JA, Childs G, Olson EN. Modulation of cardiac growth and development by HOP, an unusual homeodomain protein. Cell. 2002 Sep 20;110(6):725-35. Shin CH, Liu ZP, Passier R, Zhang CL, Wang DZ, Harris TM, Yamagishi H, Richardson JA, Childs G, Olson EN.Modulation of cardiac growth and development by HOP, an unusual homeodomain protein.Cell. 2002 Sep 20;110(6):725-35.